This invention relates to the inhibition of the abnormal accumulation of extracellular matrices; and more specifically, the invention relates to a method and cosmetic or pharmaceutical preparation for inhibiting the abnormal accumulation of extracellular matrices in dermal cells, thereby preventing or treating a disease associated with the abnormal accumulation, and the use of a certain substance for preparing such a preparation.
The transforming growth factor .beta. (TGF-.beta.) was found as a factor accelerating the transformation of cells, and thereafter, has been ascertained to act as a growth-inhibiting factor or the like on many cells. TGF-.beta. is known to exhibit many activities for example, it is considered that TGF-.beta. acts on fibroblasts, etc., accelerating the production of extracellular matrices such as collagen, and causing the abnormal accumulation of the extracellular matrices, which is a cause of various diseases.
As diseases which may be associated with such abnormal accumulation of extracellular matrices, there are mentiond, for example, fibrosis-like cancer, pulmonary fibrosis, arteriosclerosis, posterior cardiac infarction, glomerular nephritis, cardiac fibrosis, restenosis after angioplasty, renal interstitial fibrosis, keloid, scleroderma, hypertrophic scar, etc. For the purpose of treating these diseases, there have been proposed agents causing the inhibition of the synthesis of collagen, for example, peptide derivatives obtained by using the inhibition of protocollagen proline hydroxylase activity as an indication (Japanese Patent Publication No. 29740/ 1977 and Japanese Patent Publication No. 20298/1982), serine derivatives obtained by using the acceleration of the production of procollagenase as an indication (Japanese Patent Publication No. 79645/1993), etc.
However, extracellular matrices, on one hand, have relation to the regulation of physiological functions such as the adhesion, movement, growth, differentiation, etc. of cells, and thus substances screened using the inhibition of collagen synthesis as an indication cannot always be regarded as ones suitable for living bodies. Therefore, as substances for the prophylaxis or treatment of the above diseases inhibiting the extracellular matrix-producing activity of TGF-.beta. itself, there have been proposed anti-TGF-.beta. antibodies, platelet-derived growth factors (PDGF), etc.
However, it cannot always be said that a safe and effective prophylactic and treating method is established particularly against skin fibrosis such as keloid, hypertrophic scar or scleroderma, among diseases which can be regarded as ones caused by the abnormal accumulation of extracellular matrices in the skin.
Thus, the object of this invention lies in providing an agent for inhibiting the abnormal accumulation of extracellular matrices which can safely be used particularly for the prophylaxis and treatment of skin fibrosis.
The present inventors directed their attention to the phenomenon that in dermal fibroblasts activated with TGF-.beta., the production of extracellular matrices is abnormally accelerated. The inhibition of the production (or accumulation) of the matrices in such an extracellular matrix-producing system seems to reproduce the actual physical functions more faithfully and make it possible to screen substances having effectiveness and high safety, compared with the above cases, for example the case where the inhibition of collagen synthesis is merely used as an indication.
Thus, we screened agents using as an indicator the inhibitory activity on the abnormal production of extracellular matrices in dermal fibroblasts activated with TGF-.beta.. As a result we found that certain plant extracts and compounds, belonging to categories different from that to which substances have been screened using the inhibition of collagen synthesis as an indicator, have excellent inhibitory activity against the abnormal production of extracellular matrices.
Among these substances, there are included lntin-koo extract (for example, Japanese Laid-open Patent Publication No. 300812/1992 and Japanese Laid-open Patent Publication No. 65087/1994), Forsythia suspensa V.sub.AHL, extract (for example, Japanese Laid-open Patent Publication No. 152325/1984, Japanese Laid-open Patent Publication No. 207023/1990 and Japanese Laid-open Patent Publication No. 16525/1994), Sophora flavescens A.sub.ITON. or Sophora anaustifolia extract (for example, Japanese Laid-open Patent Publication No. 104005/ 1985, Japanese Laid-open Patent Publication No. 90131/ 1989, Japanese Laid-open Patent Publication No. 128934/ 1989, Japanese Laid-open Patent Publication No. 111710/ 1990, Japanese Laid-open Patent Publication No. 346917/ 1992, Japanese Laid-open Patent Publication No. 229955/ 1993 and Japanese Laid-open Patent Publication No. 25 336418/1994), and Rheum Dalmatum L. extract (for example, Japanese Laid-open Patent Publication No. 42485/ 1985, Japanese Laid-open Patent Publication No. 10006/ 1987, Japanese Laid-open Patent Publication No. 93710/ 1991, Japanese Laid-open Patent Publication No. 243834/ 1992, Japanese Laid-open Patent Publication No. 97653/ 1993 and Japanese Laid-open Patent Publication No. 207776/1995), These substances are crude drugs each exhibiting inhibitory activity on tyrosinase, lipase, hyaluronidase or the like or bacteriostatic activity and being used as a component of dermal external preparations for whitening action, for the prevention of acne vulgaris or for hair tonicity. However, there is no disclosure in past technical literatures including these official patent publication teaching that the above extracts can be used for the inhibition of the abnormal production of extracellular matrices in dermal fibroblasts, and there is no disclosure therein suggesting such use, either.